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172 Chemistry and Biology of Beta-Lactams
1
H
Sonication
1
H
Sonication
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SCHEME 5.16 Microwave-Induced and Ultrasound-Assisted Synthesis of Pyrrole-Fused Beta-Lactams.
Ar
N
2
O
SCHEME 5.17 Microwave-Induced and Ultrasound-Assisted Synthesis of Pyrrole-Fused Beta-Lactams.
N
2
O
SCHEME 5.18 Microwave-Induced and Ultrasound-Assisted Synthesis of Pyrrole-Fused Beta-Lactams.
2
+
N
Ar
H
1
Ar
2
+
N
Ar
H
1
3
3
CO
C
O
OCH
O
O
CH
3
3
Bi(NO3)
MW
or
Bi(NO3)
MW
or
3
3
N
N
O
Ar
2
N
O
Ar
Ar
2
N
Ar
reaction produced diastereomers of cis- and trans-beta-lactams. It was important to note that p-toluene
sulfonic acid under the same conditions afforded the pyrroles also in microwave-induced or sonication
reactions (Scheme 5.16).
Realizing the importance of pyrrole-substituted beta-lactams, microwave-induced and sonicationassisted reactions were extended with other starting materials. For example, 3-amino beta-lactams
reacted with 2,5-dimethoxy tetrahydrofuran in the presence of catalytic amounts of bismuth nitrate
under microwave irradiation (or under sonication), and pyrrole was isolated (Scheme 5.17).
Substituted pyrrole-fused beta-lactams were also prepared through a reaction of hexane dione and
amino beta-lactams in a microwave or in a sonicator using bismuth nitrate as the catalyst (Scheme 5.18).
Notably, a number of acidic catalysts were used successfully for this transformation [51–57]. Among
them, iodine, bismuth triate, bismuth nitrate, and p-toluene sulfonic acid were the best. The stereochemistry of the beta-lactam rings remained unaltered during this process.
5.9 Microwave-Induced and Ultrasound-Assisted
Intramolecular Oxa-Michael Reaction
Hetero-Michael’s reaction describes a nucleophilic conjugate addition of oxygen, nitrogen, and sulfur to the olenic bond.
anti-inammatory, anti-aggregating, progesterone agonist, antithrombotic, antihistaminic, anxiolytic,
antipsychotic, glycosidase inhibitor, and nitric oxide synthase [58–64]. The 1,4-dioxazepane nucleus
1–4
Seven-membered 1,4-oxazepanes have attractive bioactivity that includes
173Microwave and Ultrasound in Beta-Lactam Chemistry
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SCHEME 5.19 Synthesis of Chiral Amino-Beta-Lactams. Reagents: (a) NaIO4, (b) ArNH2, (c) N-phthaloylglycine,
2-chloro-1-methylpyridinium iodide, Et3N, (d) ethylenediamine.
SCHEME 5.20 Conversion of the Amino Group to the Unsaturated Substrate. Reagents and conditions: (a) benzaldehyde
(b) NaBH4, (c) K2CO3, THF, ethyl-(E)-4-bromobut-2-enoate and methyl-(E)-4-bromobut-2-enoate.
represents a signicant clinically active drug candidate, Sintamil, Loxapine, Batrachotoxin, and
Microline A.
A highly regio- and stereoselective method for the synthesis of beta-lactamfusedwith 1,4-oxazepanewas developed. Our study used 3-amino-beta-lactam as a chiral building block. This was obtained
from 1,2:5,6 -di-O-isopropylidene-D-mannitol. The chiral aldehyde was condensed with an aromatic
amine to get aldimine. Enantiomerically pure cis-N-phthalimido-beta-lactam was obtained using phthaloylglycine as the reactant (Scheme 5.19).
The free amino group was masked by transforming to its corresponding imine followed by sodium
borohydride reduction (Scheme 5.20). The amine was then alkylated with the unsaturated bromo ester
174 Chemistry and Biology of Beta-Lactams
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to afford the Michael acceptor. Iron (III) chloride was the best reagent for deacetonation and partial
Michael addition reaction. This result was helpful to conduct the one-pot intramolecular oxy-Michael
reaction. Potassium hydroxide was found suitable to activate the oxy-nucleophile to accomplish the
7-exo-trig-cyclization using microwave irradiation or sonicator. The annulated 1,4-oxazepane ring system was obtained (Scheme 5.21 and Scheme 5.22).
SCHEME 5.21 Michael Reaction. Reagents and conditions: (a) FeCl3, (b) KOH, THF, water, (c) TBDMSC, imidazole.
SCHEME 5.22 Cyclization by Microwave and Sonicator.
175Microwave and Ultrasound in Beta-Lactam Chemistry
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5.10 Microwave-Induced and Ultrasound-Assisted Synthesis of
Polycyclic β-Lactams by Azide-Alkyne Cycloaddition
The intramolecular azide-alkyne cycloaddition has attracted attention in synthetic chemistry. The metalfree intramolecular azide-alkyne cycloaddition in beta-lactam science was not investigated. Our synthetic protocol was based on intramolecular azide-alkyne cycloaddition reaction, which is anticipated
to lead into a highly functionalized tricyclic core structure of the β-lactams. The hydroxyl alkyne ether
of the β-lactam was produced from a sequence of chemical transformations. The hydroxyl group was
transformed into the propargyl ether by treating a suspension of the sodium hydride in anhydrous THF
(Scheme 5.23). The isopropylidene group of β-lactam was deprotected to the corresponding β-lactam
vic-diol by ferric chloride.
These diols were converted to 4-formyl β-lactams. The formyl compounds were treated with sodium
borohydride to afford the 4-hydroxymethyl β-lactams (Scheme 5.24).
The mesylate or tosylate of the alkyne was treated with sodium azide at 80–100°C for 12–24 h. The
reaction proceeded to give a fused triazolo-oxazepine β-lactam. The same reaction was conducted under
a microwave or a sonicator in toluene and gave the products. These azide-alkyne cycloadditions of terminal alkynes were performed (Scheme 5.25).
SCHEME 5.23 Chemical Manipulation of the Substrates for Cycloaddition.
SCHEME 5.24 Preparation of the Substrate for Cycloaddition.
SCHEME 5.25 Azide-Alkyne Cycloaddition by Microwave or Sonication.
176 Chemistry and Biology of Beta-Lactams
RO
Ph
RO
Ph
a:
b:
(-)-5
c
(+)-4
HO
Ph
TsO
Ph
RO
Ph
a:
b:
(-)-9
R=H
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5.11 Microwave-Induced Enzymatic Reactions on Substituted β-Lactams
Microwave-Induced Baker’s Yeast-Mediated Reactions
Microwave-induced reactions of the 3-keto group in substituted β-lactam afforded the hydroxy betalactam, the side chain of Taxol and Taxotere. In addition, chiral hydroxy β-lactams are important starting
materials for the preparation of many other molecules [65–69].
Microwave heating irradiation and enzymatic catalysis were combined in the preparation of simple
crucial molecules. Several papers explained the degradation of toxic organic pollutants using enzymes
from bacteria, fungi, and plants. The investigations on this topic contributed to minimizing the toxicity
of the pollutants and obtaining desired compounds. Therefore, microwave method with enzymatic process became an environmentally friendly method.
The reduction of keto esters to their optically active hydroxy esters was studied with free and immobilized baker’s yeast. Water and organic solvents were used in the biocatalytic processes. Glucose acted
as an electron donor and as a cofactor in baker’s yeast-induced methods. Glycerol was used for some
enzyme-induced methods.
Baker’s yeast (S. cerevisiae) was employed to reduce the keto group of α-keto-β-lactam in glycerol in
a domestic microwave. Glycerol was ideal for microwave-mediated reactions. Microwave-induced reaction of the keto-β-lactam with baker’s yeast in glycerol was conducted. Two hydroxyl compounds (cis-
and trans-isomers) were produced in a 3:1 ratio in 65% yield. The acetates were made from the hydroxyl
compounds. The cis-compounds (3R, 4S) had positive optical rotation, and the trans-compound had (3S,
4R) a negative optical rotation (Scheme 5.26). To know the absolute conguration, the tosylate was made
from a known conguration and reacted with sodium acetate (Scheme 5.27). The compound produced
by yeast reduction was identical with the product made synthetically.
These acetates showed optical purity of more than 90%. Optically active cis-β-lactam that is present
in Taxol and Taxotere was thus prepared in a microwave.
The success of this study opposed speculations that the enzymatic method cannot be performed successfully in a microwave. Rather, it conrmed that baker’s yeast is equally applicable at relatively high
SCHEME 5.26 Microwave-Induced Baker’s Yeast-Mediated Reduction.
SCHEME 5.27 Microwave-Induced Inversion of Tosylate.
O
O
Ar=
Ar=
O
Ar=
Ar=
Ph
Baker's
N
Glycerol,
Ar
p
-anisyl
p
-bromophenyl
N
Ar
p
-anisyl
p
-bromophenyl
TsCl
Py
yeast
MW
N
Ar
O
Ac
O/
2
Pyr
R=Ac
NaOAc
N
O
DMSO
Ar
O
O
NaOH/
MeOH
N
Ac
Pyr
N
Ar
2
R=A
Ar
O/
177Microwave and Ultrasound in Beta-Lactam Chemistry
Ar
O
Ar
O
A
Ar
1
Sonication
NO
2
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AcO
2
N
+
Ar
O
1
N
2
Ar
1
Lipase
Phosphate
MW
cO
SCHEME 5.28 Lipase-Catalyzed Hydrolysis of the Acetate.
SCHEME 5.29 Microwave-Induced or Sonication-Assisted Aromatic Nitration with Bismuth Nitrate-Clay.
HO
Bi(NO3)
Clay
MW
or
3
2
N
Ar
temperature in a microwave-mediated reaction process. This reduction method was signicant as this
produced chiral compound in the absence of any chiral chemical agents.
Microwave-Induced Lipase-Mediated Reactions
Different types of lipases were used to hydrolyze the 3-acetoxy group in monocyclic cis-beta-lactams
in a microwave oven [70 –72]. The temperature was kept between 40 and 50°C, and the irradiation time
was for 5–6 min. Phosphate buffer and glucose were also used along with organic solvents (mainly ethanol) as the reaction medium. A few experiments were conducted to know the progress of the reaction.
Optically pure hydroxy (product) and the unreacted acetoxy were obtained. This method is therefore an
example of a kinetic resolution (Scheme 5.28).
5.12 Microwave-Induced and Ultrasound-Assisted Facile
Nitration of the Aromatic Rings in β-Lactams
Aromatic nitration is a very useful reaction for the preparation of aromatic nitro compounds. In general,
aromatic nitration is conducted with strong nitric acid, nitric acid-sulfuric acid, and nitronium tetrauoroborate. In our study, bismuth nitrate impregnated with different types of clay was used for the nitration
of benzene, naphthalene, anthracene, pyrene, and chrysene derivatives. Mononitro derivative was the
product in most of the examples. Microwave-induced clay-impregnated bismuth nitrate was used, and
nitro derivative was obtained in comparable yield (Scheme 5.29). This reaction was also conducted using
ultrasound with equal success.
An extension of aromatic nitration was done with N-aryl beta-lactams. Under identical conditions,
p-anisyl-substituted beta-lactams were nitrated, and two isomeric products were obtained (Scheme 5.30).
This reaction afforded products with cis- and trans-substituted beta-lactams. Interestingly, this reaction
afforded the two nitro products when ultrasound was used as the energy source.
In order to identify the best condition, a study using naphthalene was conducted. A series of solids
such as montmorillonite, silica gel, alumina, and molecular sieves were investigated. Montmorillonite
was the best solid for this purpose, and the product was obtained in 90% yield. The reaction of naphthalene with silica gel as support under identical conditions afforded nitronaphthalene in lower yield. The
reaction did not give the nitro compound without microwave irradiation. Molecular sieves and acidic
alumina were unable to produce products.
Mixing the starting compounds with bismuth nitrate and montmorillonite with a polar solvent, evaporation of the solvent, and irradiation of the reaction mixture in a microwave were the conditions for
nitration. The formation of a mixture of two mononitro derivatives indicated a lesser selectivity due to
the activation of the ring by the methoxy group.
Thus, the nitration depended on the nature of the solid support. To explain this subject, the concept of
penetration depth of the solid support in the microwave oven was introduced.
178 Chemistry and Biology of Beta-Lactams
Z
Ar
3
3
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Ar
N
O
OCH
Ar
Z
N
O
OCH
SCHEME 5.30 Microwave-Induced and Ultrasound-Assisted Nitration of p-Anisyl Group in Beta-Lactams.
3
3
Bi(NO
3)3
Clay
MW
or
Sonication
Bi(NO
Clay
MW
or
Sonication
Z
3)3
Ar
N
O
Z
N
O
NO
OCH
Ar
NO
OCH
Z
+
O
2
3
Z
+
O
2
NO
N
N
2
OCH
Ar
NO
2
OCH
3
TABLE 5.1
Dielectric Constant and Penetration Depths of the 2.45 GHz Microwaves for Selected Materials
Material Penetration depth (cm) Dielectric constant
Montmorillonite 3–19 2–40
Silicon dioxide/quartz 1,000–20,000 3.5–5
Aluminum oxide 300–3,000 8.5–9
Molecular sieves/zeolites
>100
1–3
The electromagnetic radiation by the microwave enters the surface of a material [76–82]. But a part
of the radiation reects from the surface of the material, and another part penetrates inside the material.
The dipole moment, dielectric constant, and penetration index of the solid were crucial for the success
of the microwave-induced reactions. The radiation that has penetrated the material interacts with the
components of the reaction mixtures, molecules, and ions. Moreover, the radiation can penetrate the
material at various depths depending on the properties of the materials. The penetration depth values
are, therefore, important. The penetration depth of a eld is the distance from the surface of the material
to the internal point where the eld strength reduces to 1/e (=36.8%) of the original value at the surface.
The penetration depths of the 2.45 GHz microwaves for a few solids are given in Table 5.1. A lower
penetration depth of the solid support was helpful for the aromatic nitration. Therefore, montmorillonite
(3–19 cm) acted as a superior support for nitration. Due to the small penetration depth compared to other
solids, electromagnetic radiation penetrates only a small distance. So, a controlled and effective heating
takes place with montmorillonite. The controlled and efcient heating was able to generate products in
a superior way compared to bulk heating of the whole reactants. On this basis, silicon dioxide or quartz,
alumina, and molecular sieves were not effective, because of their high penetration depth. These four
solids have comparable low dielectric constant. The results indicated that the dielectric constant is less
crucial in nitration under the microwave [83]. The binding of bismuth nitrate to the hydroxyl groups of
the montmorillonite was important for nitration reaction. The lower penetration depth of the montmorillonite was helpful to produce nitronium ions effectively.
5.13 Microwave-Induced and Ultrasound-Assisted
Hydrogenation in Beta-Lactams
In continuation of our research strategy in using beta-lactams for the synthesis of diverse molecules,
unprecedented results based on ultrasound- and microwave-induced hydrogenation reaction were developed. Hydrogenation and hydrogenolysis with metal-mediated processes are fundamental reactions. This
reaction was performed, in general, with metal catalysts (palladium, platinum, nickel, and rhodium)
179Microwave and Ultrasound in Beta-Lactam Chemistry
r
XArZ
-Cleavage
O
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3
2
N Y
R
1
a
1
4
O
1-C2
N
(O)-Cleavage
R
Z
Ar
+
N
R
1
O
ArZ
4
3
N
2
1
R
1
1
N
Z
+
O
A
Y
a
4
Ar N
3
1
R
1
2
ZOX
4
1
N
-C
FIGURE 5.3 Microwave or sonication-induced possible bond cleavage in beta-lactam ring.
and hydrogen gas applying pressure [84–87]. Researchers used different other sources to overcome the
ammability and danger during chemical reaction with hydrogen gas. A few of these procedures became
popular. These methods used sodium formate, Raney nickel, hydrazine, cyclohexadiene, and cyclohexene as the alternative source of hydrogen.
The cleavage of the N1–CO bond in certain beta-lactams was facile, and this was easily achieved by
the attack of nucleophiles. There were other possibilities of beta-lactam ring cleavage routes. The most
probable was N1–C4 bond cleavage, and it was used for the synthesis of α-amino acid, hydroxy acid,
polyamides, and polyamino-alcohol (Figure 5.3).
Ultrasound-induced hydrogenolysis of β-lactams with C4 aryl groups was conducted by ammonium
formate and Pd/C. This reaction produced open-chain amides as the products in excellent yield. This
procedure was fast. But sterically hindered polyaromatic β-lactams did not undergo N1–C4 bond breakage following this method. In catalytic hydrogenation, hydrogen gas was used. Hydrogen gas in the presence of metals is re sensitive. It is necessary to remove unused hydrogen gas from the reaction mixture
by a pump to prevent explosion or re. In catalytic transfer hydrogenation procedure, a hydrogen gas
donor is used at different temperature.
Ultrasound-mediated catalytic transfer hydrogenation reaction proceeds smoothly at 40°C, and the
amides were obtained within 10 min (Scheme 5.31). Table 5. 2 indicates numerous examples.
To extend the method and to correlate the anticancer activity of the amides, an attempt was made
to cleave the N1–C4 bond of trans-N-ch rysen yl-3- aceto xy-4- pheny l-2-a zetid inone and trans-N-ch rysen
yl-3- pheno xy-4- pheny l-2-a zetid inone following ultrasound–hydrogenation method. No N1–C4 bond
cleavage occurred in these substrates. Microwave irradiation method was also conducted using 10%
180 Chemistry and Biology of Beta-Lactams
MW
O
Z
HH
2
No reaction
2
OBn,
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=
Z
Ar
N
R
O
NH
.HCO
4
2
II
1
Pd
Ultrasound
or
(S)
Ar
Z
1
R
N
H
OAc, OBn,
=
Z
OAc, OH,
NH
NH
2
SCHEME 5.31 Synthesis of Hydroxy/Amino-N-Arylamide by Hydrogenation Using Ultrasound.
TABLE 5.2
Synthesis of Racemic Hydroxy/Amino-N-Arylamides by PalladiumInduced Catalytic Hydrogenation Under Ultrasound Irradiation
C6H
C6H
C6H
1
5
5
5
Z Condition(s) Yieldb [%]
NH
OH
OAc
4-MeO-C6H4NH
4-MeO-C6H4OH
4-MeO-C6H4OAc
NH
OH
OAc
NH
OH
OAc
NH
OH
OAc
C6H
C6H
C6H
C6H
C6H
C6H
5
5
5
5
5
5
5
5
5
40°C, 7 min
2
40°C, 8 min
40°C, 7 min
40°C, 7 min
2
40°C, 8 min
40°C, 7 min
40°C, 8 min
2
40°C, 8 min
40°C, 8 min
40°C, 7 min
2
40°C, 8 min
40°C, 8 min
40°C, 8 min
2
40°C, 8 min
40°C, 8 min
74
84
91
88
83
90
87
80
85
85
84
90
85
87
90
Entry Ar R
1 C6H
2 C6H
3 C6H
4 C6H
5 C6H
6 C6H
5
5
5
5
5
5
7 4-MeO-C6H4C6H
8 4-MeO-C6H4C6H
9 4-MeO-C6H4C6H
10 4-F-C6H
11 4-F-C6H
12 4-F-C6H
13 4-Me-C6H
14 4-Me-C6H
15 4-Me-C6H
4
4
4
4
4
4
SCHEME 5.32 Attempted Cleavage of N1–C4 Bond in Polyaromatic Beta-Lactams.
Pd/C and ammonium formate at 80°C. But no open-chain amides were formed (Scheme 5.32). The
bulkier aromatic group was able to exert a severe stearic hindrance, which impedes the approach of the
hydrogen radical to cleave the N1–C4 bond.
Mechanistically, these results were explained assuming the formation of a radical by the attack of palladium. Palladium was able to assist a homolytic cleavage of benzylic proton of beta-lactam structure (I).
A subsequent homolysis of the C–N bond produced a nitrogen radical (II). An intermediate III adopted
route I to give amide (IV) in good yield when monocyclic aromatic rings were present in N of the ring.
The driving force was due to the stabilization of nitrogen radical through back donation of the electron
loan pair of carbonyl oxygen to the empty p-orbital. Polyaromatic ring exerted a greater steric hindrance,
and as a result, stabilization of radical intermediate was hindered. In addition, it appeared that polyconjugated system prefers pi stacking rather than stabilizing the nitrogen radical (Scheme 5.33).
Ar
H
4
Z H
Z = NH
NH
.HCO
4
or
Pd
2
II
MW
N
1
O
Ultrasound
,
OAc
R
HH
Pd
I
Ar
Br
Sonication
Ar
1
Ar
Sonication
O
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2
N
1
R
O
III III
SCHEME 5.33 Mechanism of Hydrogenation.
H
2
R
O
181Microwave and Ultrasound in Beta-Lactam Chemistry
H
H
H
H
2
R
N
1
R
Route b
N
O
R
Route
1
2
R
a
H
N
O
1
R
IV
R
C
COOEt
H
SCHEME 5.34 Microwave and Ultrasound-Induced Reformatsky Reaction Toward Beta-Lactams.
Z
Br
N
SCHEME 5.35 Microwave- and Ultrasound-Induced Radical Cyclization.
2
+
Ar
1
Bu
SnH
3
AIBN
MW
or
In,
MW
THF
or
R
N
Ar
O
Z
N
O
CH
R
2
+
O
1
Z
+
3
N
O
2
N
Ar
5.14 Microwave- and Ultrasound-Induced Indium-
Mediated Reaction Toward β-Lactams
Indium metal was used for the synthesis of beta-lactams by reacting bromoethyl acetate with imines in a
microwave or ultrasound instrument. Substituted bromoester produced a mixture of cis- and trans-betalactams in almost 1:1 proportion (Scheme 5.34) [88–90]. In some instances and particularly with N-aryl
imines, intermediates of beta-amino esters were obtained. These beta-amino esters were cyclized to
beta-lactams by Grignard reagent.
Cyclization Toward Polycyclic β-Lactams
To investigate a radical cyclization method, substituted alkenyl beta-lactams with bromoaryl system
were rst prepared. Tributyltin hydride and AIBN were used as reagents in the intramolecular cyclization of these types of compounds in a microwave as well as in an ultrasound instrument (Scheme 5.35)
[91, 92]. It appeared that the aryl radical formed was cyclized with the olenic group through exo and
endo mode giving a mixture of products. The stereochemistry of the products remained unaltered during
this transformation.
5.15 Microwave- and Ultrasound-Induced Radical
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